19-4816406-G-A

Variant names:

• chr19-4816406-G-A
• rs1292695561
• NM_182919.4:c.1972C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_182919.4(TICAM1):​c.1972C>T​(p.Pro658Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000352 in 1,418,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P658L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: TICAM1 NM_182919.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.660
• Publications: 0 publications found

Genes affected

TICAM1 (HGNC:18348): (TIR domain containing adaptor molecule 1) This gene encodes an adaptor protein containing a Toll/interleukin-1 receptor (TIR) homology domain, which is an intracellular signaling domain that mediates protein-protein interactions between the Toll-like receptors (TLRs) and signal-transduction components. This protein is involved in native immunity against invading pathogens. It specifically interacts with toll-like receptor 3, but not with other TLRs, and this association mediates dsRNA induction of interferon-beta through activation of nuclear factor kappa-B, during an antiviral immune response. Mutations in this gene are associated with encephalopathy, acute, infection-induced. [provided by RefSeq, Jul 2020]

TICAM1 Gene-Disease associations (from GenCC):

• herpes simplex encephalitis, susceptibility to, 4

  Inheritance: AR, AD, SD Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06351262).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182919.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TICAM1	NM_182919.4	MANE Select	c.1972C>T	p.Pro658Ser	missense	Exon 2 of 2	NP_891549.1	Q8IUC6
	TICAM1	NM_001385678.1		c.1930C>T	p.Pro644Ser	missense	Exon 3 of 3	NP_001372607.1
	TICAM1	NM_001385679.1		c.1837C>T	p.Pro613Ser	missense	Exon 2 of 2	NP_001372608.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TICAM1	ENST00000248244.6	TSL:1 MANE Select	c.1972C>T	p.Pro658Ser	missense	Exon 2 of 2	ENSP00000248244.4	Q8IUC6
	TICAM1	ENST00000868535.1		c.1972C>T	p.Pro658Ser	missense	Exon 3 of 3	ENSP00000538594.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000488 AC: 1 AN: 205056 AF XY: 0.00000913

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000591

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000352 AC: 5 AN: 1418476 Hom.: 0 Cov.: 36 AF XY: 0.00000427 AC XY: 3 AN XY: 702342

African (AFR) AF: 0.00 AC: 0 AN: 32048

American (AMR) AF: 0.0000269 AC: 1 AN: 37222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22698

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39470

South Asian (SAS) AF: 0.00 AC: 0 AN: 78740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5448

European-Non Finnish (NFE) AF: 0.00000274 AC: 3 AN: 1093144

Other (OTH) AF: 0.00 AC: 0 AN: 58556

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Herpes simplex encephalitis, susceptibility to, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	2.9
DANN	Benign	0.45
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.66
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.012
Sift	Benign	0.20	T
Sift4G	Uncertain	0.036	D
Polyphen		0.0	B
Vest4		0.064
MutPred		0.42		Gain of glycosylation at P658 (P = 0.0138)
MVP		0.17
MPC		0.24
ClinPred		0.020	T
GERP RS		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.039
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1292695561; hg19: chr19-4816418;